The cancer chemopreventive and chemotherapeutic role of retinoids has been demonstrated in a variety of studies. However, the clinical usefulness of retinoid therapies is not likely to be fully realized until basic aspects of their metabolism are better understood. Thus, the general focus of work in our laboratory has been twofold: first, to investigate at the molecular, tissue and whole body level, the mechanisms involved in the normal physiological metabolism of vitamin A. Secondly, we examined the effects of chemopreventive retinoids on normal vitamin A metabolism. Several long-term studies of retinol kinetics were performed in animals fed N-[4-hydroxyphenyl] retinamide (4-HPR) or all-trans-retinoic acid. Following IV injection of a physiologically radiolabeled dose of retinol, retinol tracer and tracee kinetics were monitored in plasma and tissues for up to 41 days. Kinetic parameters were determined using the SAAM/CONSAM computer modeling programs to carry out graphical analysis of tracer concentration curves. Analysis of data from the 4-HPR study demonstrated major alterations of "native" vitamin A metabolism. Mean plasma retinol levels were reduced in the 4-HPR group to one-third of controls. The fraction of the plasma retinol catabolized per day was nearly twice as high in the 4-HPR treated group. The amount of time that retinol molecules spent in the plasma before being lost from the system was cut nearly in half in the 4-HPR treated group and the amount of vitamin A retinol ultimately utilized in these animals was 33% less than that used by the control group. Studies investigating the mechanisms by which 4-HPR alters retinol kinetics are presently underway in our laboratory. The results thus far would suggest that long-term administration of 4-HPR markedly perturbs normal retinol metabolism in rats. Whether 4-HPR similarly alters human retinol metabolism with untoward clinical consequences deserves careful evaluation. We are presently developing the appropriate methodology using stable isotope forms of vitamin A to carry out turnover studies in humans.